This proposal focuses on understanding the neurobiological mechanisms of resilience to stress-related disorders. Because stress-related disorders--including depression, post-traumatic stress disorder and childhood cognitive and emotional defects that follow neglect and abuse--affect a significant proportion of children and adults and exact a huge human potential and financial toll, understanding the processes that engender resilience to these disorders carries profound impact. Vulnerability and resilience to disease are governed by the interaction of genes and environment / experience. Importantly, experience during early postnatal life influences the expression of stress-related genes, which may promote resilience or vulnerability to stress-related disorders. However, little is known about how these important effects take place. Augmenting early life experience by enhancing maternal care in the rat results in persistent alterations of stress-related genes: reduced expression of hypothalamic corticotropin releasing hormone (CRH) was found by the applicant already by the end of the enriched-experience period on postnatal day 9, preceding attenuation of stress responses and increased expression of hippocampal glucocorticoid receptor (GR). In addition, reducing CRH-CRH-receptor signaling in immature non-enriched rats was sufficient to up-regulate hippocampal GR persistently and to confer enduring resilience to stress. These findings indicate that repression of hypothalamic Crh gene expression is an early and crucial step in the molecular cascade bridging enriched maternal-derived early-life experience and the enduring neuroplasticity of the stress system that promotes resilience to stress-related disorders. The current proposal addresses important gaps in our understanding of the process by which augmented sensory input from maternal care promotes resilience to stress-related disorders: how are maternal-derived signals converted to information that 'commands' hypothalamic neurons to repress Crh gene expression? What molecular mechanisms initiate this repression? Maintain it throughout life? The aims of the proposed research are to (1) Test the hypothesis that augmented early-life maternal-care initiates epigenetic programming of the Crh gene via increased expression of the transcriptional repressor Neural Restrictive Silencing Factor (NRSF) and increased NRSF binding to a cognate binding site (NRSE) in the regulatory region of Crh. (2) Test the hypothesis that NRSF binding to NRSE is required for repression of Crh gene expression in hypothalamic neurons from experience-enriched rats. (3) Employ controlled, in vitro systems to test the hypothesis that NRSF upregulation and Crh repression in hypothalamic neurons are a result of reduced excitatory synaptic input to these neurons. (4) Examine the mechanisms that may be responsible for the maintenance of the suppressed expression of CRH and consequent attenuated stress responses and resilience to stress-related disorders. In summary, resilience to stress-related disorders is of major clinical significance. The paramount contribution of early-life experience to this resilience can be studied in suitable animal models, and information is now available regarding the molecular and functional changes of the 'stress system' that contribute to resilience. The proposed research will define how these molecular changes are initiated and maintained, and identify potential targets for translational clinical use, with profound impact on human health.